A single base mutation that converts glycine 907 of the α2(I) chain of type I procollagen to aspartate in a lethal variant of osteogenesis imperfecta. The single amino acid substitution near the carboxyl terminus destabilizes the whole triple helix

Abstract

Type I procollagen was examined in cultured skin fibroblasts from a patient with a lethal variant of osteogenesis imperfecta. About half of the pro-α chains were post-translationally overmodified and had a decreased thermal stability. The vertebrate collagenase A fragment had a normal thermal stability, but the B fragment had a decreased thermal stability. Therefore, there was a change in primary structure in amino acids 776-1014 of either the α1(I) or α2(I) chain. Three of five cDNA clones for the α2(I) chain contained a single-base substitution of an A for a G that converted the codon for glycine at amino acid position 907 to aspartate. Complete nucleotide sequencing of bases coding for amino acids 776 to 1014 of the α2(I) chain was carried out in one cDNA clone that contained the mutation in the glycine codon and in one that did not. Also, nucleotide sequencing was performed of bases coding for amino acids 776-1014 of the α1(I) chain in seven independent cDNA clones. No other mutations were found. Therefore, the single base substitution that converts glycine 907 in the α2(I) chain to aspartate is solely responsible for the decreased thermal stability of the type I procollagen synthesized by the proband's fibroblasts. Also, glycine 907 of the α2(I) chain is an important component of a cooperative block that determines the melting temperature of the whole molecule.